caa a22 4500 467938962 CHVBK 20180406153006.0 cr unu---uuuuu 170328e20060501xx s 000 0 eng 10.1007/s10822-006-9059-x doi (NATIONALLICENCE)springer-10.1007/s10822-006-9059-x Do benzodiazepines mimic reverse-turn structures? [Elektronische Daten] [Masayuki Hata, Garland R. Marshall] The role of benzodiazepine derivatives (BZD) as a privileged scaffold that mimics β-turn structures (Ripka etal. (1993) Tetrahedron 49:3593-3608) in peptide/protein recognition was reexamined in detail. Stable BZD ring conformers were determined with MM3, and experimental reverse-turn structures were extracted from the basis set of protein crystal structures previously defined by Ripka etal. Ideal β-turns were also modeled and similarly compared with BZD conformers. Huge numbers of conformers were generated by systematically scanning the torsional degrees of freedom for BZDs, as well as those of ideal β-turns for comparison. Using these structures, conformers of BZDs were fit to experimental structures as suggested by Ripka etal., or modeled classical β-turn conformers, and the root-mean-square deviation (RMSD) values were calculated for each pairwise comparison. Pairs of conformers with the smallest RMSD values for overlap of the four α-β side-chain orientations were selected. All overlaps of BZD conformers with experimental β-turns yielded one or more comparisons where the least RMSD was significantly small, 0.48-0.86Å, as previously suggested. Utilizing a different methodology, the overall conclusion that benzodiazepines could serve as reverse-turn mimetics of Ripka etal. is justified. The least RMSD values for the overlap of BZDs and modeled classical β-turns were also less than 1Å. When comparing BZDs with experimental or classical β-turns, the set of experimental β-turns selected by Ripka etal. fit the BZD scaffolds better than modeled classical β-turns; however, all the experimental β-turns did not fit a particular BZD scaffold better. A single BZD ring conformation, and/or chiral orientation, can mimic some, but not all, of the experimental β-turn structures. BZD has two central ring conformations and one chiral center that explains why the four variations of the BZD scaffold can mimic all types of β-turn structure examined. It was found, moreover, that the BZD scaffold also mimics each of the nine clusters of experimental orientations of side chains of reverse turns in the Protein Data Bank, when the new classification scheme for the four side-chain directions (the relative orientations of α-β vectors of residues i through i+3) was considered (Tran etal. (2005) J Comput-Aided Mol Des 19:551-566). Springer Science+Business Media B.V., 2006 Reverse turn nationallicence Beta-turn nationallicence Benzodiazepine nationallicence Privileged scaffold nationallicence Peptidomimetic nationallicence Conformational mimicry nationallicence Systematic search nationallicence Hata Masayuki Center for Computational Biology, Washington University School of Medicine, 700 S. Euclid Ave., 63110, St. Louis, MO, USA aut Marshall Garland R. Center for Computational Biology, Washington University School of Medicine, 700 S. Euclid Ave., 63110, St. Louis, MO, USA aut Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/5(2006-05-01), 321-331 0920-654X 20:5<321 2006 20 10822 https://doi.org/10.1007/s10822-006-9059-x text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10822-006-9059-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Hata Masayuki Center for Computational Biology, Washington University School of Medicine, 700 S. Euclid Ave., 63110, St. Louis, MO, USA aut NATIONALLICENCE 700 1- Marshall Garland R. Center for Computational Biology, Washington University School of Medicine, 700 S. Euclid Ave., 63110, St. Louis, MO, USA aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/5(2006-05-01), 321-331 0920-654X 20:5<321 2006 20 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer